Immunological tolerance reflects complex interactions amongst multiple cells and it is tailored to specific challenges that arise during development. For example, in the digestive tract, Th cells limit the host response to dietary or microbial antigens that are introduced into the lumen during neonatal life. The importance of appropriate immune responses to enteric flora is illustrated in mouse models in which Helicobacter hepaticus induces regulatory Th cells (Treg) in normal mice while exacerbating intestinal inflammation in animals in which regulatory T cell function is perturbed. Studies suggest that chronic, relapsing inflammatory bowel diseases (IBD) in humans result from inappropriately regulated immune responses to enteric antigens in genetically susceptible hosts. The exact etiology and pathogenesis of IBD is unclear but there is substantial interest in the role of [unreadable]natural[unreadable] or [unreadable]acquired[unreadable] Treg in intestinal immune regulation. Therefore, it is essential to understand the factors regulating the development of tolerance to luminal flora during the neonatal period as they may influence the risk of developing IBD later in life. One factor that mediates anti-inflammatory activity is adenosine. Adenosine accumulates in inflamed or hypoxic tissues largely due to CD39 mediating the dephosphorylation of ATP to ADP then to 5[unreadable]-AMP while CD73 catalyzes the terminal reaction to convert 5[unreadable]AMP to adenosine. Activation of A2A adenosine receptors (A2AAR) on T cells produces a series of responses that have been categorized as anti-inflammatory. Our lab discovered that regulatory T cells controlling inflammatory responses in the colon are directly dependent on the presence of the A2AAR. We propose the general hypothesis that adenosine accumulates during Th cell activation and regulates the function of both Treg and effector Th subsets. More specifically, we suggest that the development of acquired tolerance during the post-weaning period is modulated by the A2AAR expressed by Th cells. The objective of this proposal is to understand the untested and novel concept that A2AAR contribute to the development of T cells [unreadable] such as acquired Treg - that confer immune tolerance. The specific aims are: Aim 1. Define the effects of adenosine accumulation on the function of Th cell subsets. Aim 2. Examine the role of the A2A adenosine receptor in Th cell development. Together, these studies will investigate an innovative and complementary model for the control of effector T cell function that can be exploited pharmacologically for the treatment of chronic inflammatory diseases such as IBD.